Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), is a dominantly inherited neurological disorder characterized by progressive difficulties with coordination and brainstem function. SCA3/MJD is one of at least eight neurodegenerative diseases now known to be caused by an expanded CAG repeat that encodes a polyglutamine domain in the disease protein. Increasing evidence indicates that expanded polygln in itself the factor that is toxic to neurons in these diseases, and that this toxicity stems from polygln s tendency to misfold and aggregate. The overall goal of the proposed studies is to determine the mechanism of neuronal death in this group of diseases. Our hypothesis is that misfolding and aggregation of the disease protein within the nucleus of the neuron is the underlying toxic event in these diseases. The proposed experiments aim to answer how misfolding and aggregation of the SCA3/MJD disease protein compromises cellular function, ultimately leading to cell death. Studies will: 1) characterize the metabolic consequences of polyglutamine misfolding and aggregation; 2) address whether aggregates are a cause or consequence of the disease process; and 3) characterize genetic and cellular factors that modify polygln aggregation and toxicity. The proposed experiments should provide insight into the common mechanism underlying an important group of inherited human diseases, and may identify potential targets for therapeutic intervention in SCA3/MJD and related neurological disorders. Moreover, because protein misfolding is now recognized to be central to many of the most common forms of neurodegenerative disease (including Alzheimer and Parkinson disease), the proposed studies may prove to be relevant more broadly to such diseases as well.